Neuroglial Cb1 Receptors Control Navigation Strategies

Navigation and memory functions are essential for survival and are regulated by the hippocampus. These processes are tightly controlled, and one of the key modulators involved is the endocannabinoid system, particularly through the cannabinoid receptor type-1 (CB1). CB1 is widely expressed in various hippocampal cell types. While it is known that CB1 participates in memory processes, its specific roles in different cell types and how these roles may differ between sexes remain unclear. This study investigates how CB1 signaling in the hippocampus, in both, cell-type-specific and sex-dependent manner, contributes to navigation and memory. To this end, we selectively deleted CB1 receptors from neurons, CAMKII-expressing neurons, and astrocytes from the hippocampus of adult male and female mice. We then assessed its effect on a broad range of behaviors, including innate emotional responses, memory, navigation, and other hippocampus-related functions such as nesting. Deletion of CB1 in CAMKII-expressing neurons produced a pronounced effect in males, leading to increased anxiety and impairments in both reference and spatial memory. These mice also showed altered performance in the Barnes maze, relying less on spatial strategies. By contrast, females were less affected by this specific deletion. Interestingly, only deletion of CB1 from astrocytes led to spatial memory impairments in females, which also showed reduced LTP and a decreased reliance on spatial strategies in the Barnes maze. In conclusion, our findings show that neuronal CB1 receptors are critical for the spatial navigation strategy in males, while astrocytic CB1 receptors play a key role in memory processes both in males and females.